U.S. patent application number 09/964415 was filed with the patent office on 2003-05-01 for adhesive compositions containing dual function stabilizers and active agents.
This patent application is currently assigned to CLOSURE MEDICAL CORPORATION. Invention is credited to Badejo, Ibraheem, McAfoos, Timothy, Sherbondy, Anthony.
Application Number | 20030082116 09/964415 |
Document ID | / |
Family ID | 25508517 |
Filed Date | 2003-05-01 |
United States Patent
Application |
20030082116 |
Kind Code |
A1 |
Badejo, Ibraheem ; et
al. |
May 1, 2003 |
Adhesive compositions containing dual function stabilizers and
active agents
Abstract
An adhesive composition includes a polymerizable adhesive
monomer and at least one dual function stabilizer. The stabilizer
provides superior stabilization and shelf-life of the composition,
and enhances wound healing properties of the monomer
composition.
Inventors: |
Badejo, Ibraheem;
(Morrisville, NC) ; Sherbondy, Anthony; (Raleigh,
NC) ; McAfoos, Timothy; (Wooster, OH) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. BOX 19928
ALEXANDRIA
VA
22320
US
|
Assignee: |
CLOSURE MEDICAL CORPORATION
Raleigh
NC
|
Family ID: |
25508517 |
Appl. No.: |
09/964415 |
Filed: |
September 28, 2001 |
Current U.S.
Class: |
424/58 ; 424/728;
424/730; 424/736; 424/745; 424/748; 424/754; 424/757; 424/764;
424/765; 424/770; 523/120 |
Current CPC
Class: |
A61L 2300/21 20130101;
A61L 24/0005 20130101; A61K 36/185 20130101; C09J 4/00 20130101;
A61L 2300/41 20130101; A61L 2300/30 20130101; A61L 24/06 20130101;
A61L 24/0015 20130101; A61K 45/06 20130101; A61K 36/88 20130101;
A61K 36/185 20130101; A61K 2300/00 20130101; A61K 36/88 20130101;
A61K 2300/00 20130101; A61L 24/06 20130101; C08L 35/04 20130101;
C09J 4/00 20130101; C08F 222/326 20200201 |
Class at
Publication: |
424/58 ; 523/120;
424/728; 424/730; 424/764; 424/765; 424/745; 424/748; 424/770;
424/736; 424/757; 424/754 |
International
Class: |
A61K 007/26; A61K
035/78 |
Claims
What is claimed is:
1. An adhesive composition comprising: a polymerizable
1,1-disubstituted ethylene monomer; and at least one stabilizer
selected from the group consisting of herbal extracts, alpha- and
beta- hydroxycarboxylic acids and salts thereof, ceramides,
anti-inflammatories, vasoconstrictors, and mixtures thereof.
2. The composition of claim 1, wherein said stabilizer is an herbal
extract.
3. The composition of claim 2, wherein said herbal extract is an
oil-soluble herbal extract.
4. The composition of claim 3, wherein said herbal extract is
selected from the group consisting of chamomile, carrot root,
echinacea purpurea, fennel, ginseng, grape seed, grape skin,
grapefruit, guggalipids, harpogophytum, jasmine, marjoram, myrrh
gum resin, onion, pine bark, red clover flower, resveratrol,
rosemary, sesame, St. Johns wort, thyme, Uva Ursi (bearberry),
borage seed oil, wild borage seed oil, hesperedin, quercetin,
kaempherol, genistein, coumestrol, estriol, phytosterols, limonene,
ethoxyquin, hydroquinone, ubiquinone (coenzyme Q), lipoic acid,
N-acetyl cysteine, curcumin, basil leaf, bell pepper, dandelion
root, date palm fruit, licorice, tomato, myricetin, derivatives
thereof, and mixtures thereof.
5. The composition of claim 3, wherein said herbal extract is
selected from the group consisting of chamomile, carrot root,
echinacea purpurea, fennel, ginseng, grape seed, grape skin,
grapefruit, guggalipids, harpogophytum, jasmine, marjoram, myrrh
gum resin, onion, pine bark, red clover flower, resveratrol,
rosemary, sesame, St. Johns wort, thyme, Uva Ursi (bearberry),
borage seed oil, wild borage seed oil, hesperedin, quercetin,
kaempherol, genistein, coumestrol, estriol, phytosterols, limonene,
ethoxyquin, hydroquinone, ubiquinone (coenzyme Q), lipoic acid,
N-acetyl cysteine, curcumin, derivatives thereof, and mixtures
thereof.
6. The composition of claim 3, wherein said herbal extract is
selected from the group consisting of dill, horseradish, oats,
neem, beet, broccoli, tea, pumpkin, soybean, barley, walnut, flax,
ginseng, poppy, avocado, pea, sesame, dandelion, wheat, nettle,
cashew, pineapple, apple, asparagus, Brazilnut, chickpea,
grapefruit, orange, cucumber, buckwheat, strawberry, ginko, tomato,
blueberry, cowpea, grape extracts, ivy horse chestnut, centella
asiatica, rosmarinic acid, glycyrrizinate derivatives, alpha
bisabolol, azulene, asiaticoside, sericoside, ruscogenin, escin,
escolin, betulinic acid, catechin, derivatives thereof, and
mixtures thereof.
7. The composition of claim 1, wherein said stabilizer is curcumin
or a curcumin derivative.
8. The composition of claim 7, wherein said stabilizer is selected
from the group consisting of curcumin, demethoxycurcumin,
bisdemethoxycurcumin, tetrahydrocurcumin,
tetrahydrodemethoxycurcumin, tetrahydrobisdemethoxycurcumin, other
curcumin metabolites, (4-hydroxy-3-methoxycinnamoyl)methane,
bis(4-hydroxycinnamoyl)methane, hexahydrocurcumin,
octahydrocurcumin, and mixtures thereof.
9. The composition of claim 1, wherein said stabilizer is an alpha-
or beta-C.sub.1-C.sub.30 hydroxycarboxylic acid or salt
thereof.
10. The composition of claim 9, wherein said stabilizer is selected
from the group consisting of alpha- and beta-C.sub.1-C.sub.30
hydroxycarboxylic acids and salts thereof.
11. The composition of claim 9, wherein said stabilizer is selected
from the group consisting of salicylic acid, alpha hydroxy acetic
acid, alpha hydroxybenzeneacetic acid, alpha hydroxypropionic acid,
alpha hydroxybutanoic acid, alpha hydroxyhexanoic acid, alpha
hydroxyoctanoic acid, alpha hydroxynonanoic acid, alpha
hydroxydecanoic acid, alpha hydroxyundecanoic acid, alpha
hydroxydodecanoic acid, alpha hydroxytetradecanoic acid, alpha
hydrocyhexadecanoic acid, alpha hydroxyoctadecanoic acid, alpha
hydroxyoctaeicosanoic acid, dicarboxylic alpha hydroxy acids,
dihydroxybutanedioic acid (tartaric acid), 2-hydroxybutanedioic
acid, 2-hydroxy propanedioic acid, 2-hydroxy hexanedioic acid,
2-hydroxy octanedioic acid, 2-hydroxy decanedioic acid, 2-hydroxy
dodecanedioic acid, 2-hydroxy myristicdioic acid, 2-hydroxy
palmiticdioic acid, tricarboxylic alpha hydroxy acid,
2-hydroxy-1,2,3,-propanetricarboxylic acid,
1-hydroxy-1,2,3-propanetricar- boxylic acid, and mixtures
thereof.
12. The composition of claim 1, wherein said stabilizer is a
ceramide.
13. The composition of claim 12, wherein said ceramide is selected
from the group consisting of Ceramide 1, Ceramide 3, Ceramide 6,
and mixtures thereof.
14. The composition of claim 1, wherein said stabilizer is an
anti-inflammatory.
15. The composition of claim 14, wherein said anti-inflammatory is
selected from the group consisting of beta-methasone 17-acetate,
indomethacin, ketoprofen, flufenamic acid, ibuprofen, diclofenace,
diflunisal, fenclofenac, naproxen, piroxidam, sulindac, and
mixtures thereof.
16. The composition of claim 1, wherein said stabilizer is a
vasoconstrictor.
17. The composition of claim 16, wherein said vasoconstrictor is
selected from the group consisting of papaverine, yohimbine,
visnadin, khellin, bebellin, nicotinate derivatives, and mixtures
thereof.
18. The composition of claim 1, wherein said monomer is an
.alpha.-cyanoacrylate.
19. The composition of claim 1, wherein said monomer is at least
one member selected from the group consisting of methyl
cyanoacrylate, ethyl cyanoacrylate, n-butyl cyanoacrylate, 2-octyl
cyanoacrylate, methoxyethyl cyanoacrylate, ethoxyethyl
cyanoacrylate, hexyl cyanoacrylate, dodecyl cyanoacrylate, butyl
lactoyl cyanoacrylate, butyl glycoloyl cyanoacrylate, ethyl lactoyl
cyanoacrylate, and ethyl glycoloyl cyanoacrylate.
20. The composition of claim 1, wherein said stabilizer is present
in said composition in a concentration of from about 0.01 to about
10.0% by weight.
21. The composition of claim 1, wherein said stabilizer is present
in said composition in a concentration of from about 0.01 to about
5.0% by weight.
22. The composition of claim 1, wherein said composition has a
Sterility Assurance Level of not better than 10.sup.-3.
23. The composition of claim 1, wherein said composition is
sterilized to a Sterility Assurance Level of at least
10.sup.-3.
24. The composition of claim 1, further comprising a non-stabilizer
medicament.
25. The composition of claim 1, further comprising a
plasticizer.
26. The composition of claim 1, wherein said stabilizer is present
in an amount sufficient to stabilize said composition during
sterilization.
27. The composition of claim 1, wherein said stabilizer is present
in an amount sufficient to stabilize said composition during and
subsequent to sterilization.
28. The composition of claim 1, wherein said stabilizer is present
in an amount effective to provide wound healing when said
composition is applied to a tissue surface.
29. The composition of claim 1, wherein said composition further
comprises at least one antioxidant stabilizer.
30. The composition of claim 29, wherein said at least one
antioxidant stabilizer is selected from the group consisting of
vitamin E and derivatives thereof, vitamin K and derivatives
thereof, vitamin C, pentamethyl chromanol, non-phenolic
antioxidants, octyl gallate, and pentamethylbenzofuranol.
31. The composition of claim 29, wherein said at least one
antioxidant stabilizer is pentamethyl chromanol.
32. A method of making the adhesive composition of claim 1,
comprising combining the polymerizable 1,1-disubstituted ethylene
monomer and the stabilizer.
33. A method of making a sterile polymerizable 1,1-disubstituted
monomer adhesive composition comprising: dispensing the
polymerizable 1,1-disubstituted monomer adhesive composition of
claim 1 into a container; sealing said container; and sterilizing
the composition in the container.
34. A method of making a sterile polymerizable 1,1-disubstituted
monomer adhesive composition comprising: dispensing a polymerizable
1,1-disubstituted monomer adhesive composition into a container;
sealing said container; and sterilizing the composition in the
container to a Sterility Assurance Level of at least 10.sup.-3,
wherein said polymerizable 1,1-disubstituted monomer composition
comprises: a polymerizable 1,1-disubstituted ethylene monomer; and
at least one stabilizer selected from the group consisting of
herbal extracts, alpha- and beta-hydroxycarboxylic acids and salts
thereof, ceramides, anti-inflammatories, vasoconstrictors, and
mixtures thereof.
35. The method of claim 34, wherein said sterilizing is by dry
heat, gamma irradiation, electron beam irradiation, or microwave
irradiation.
36. The method of claim 34, wherein said sterilizing is by electron
beam irradiation.
37. The method of claim 34, wherein said sterilizing is by gamma
irradiation.
38. The method of claim 34, wherein the sterilized composition has
a viscosity less than 150% of a viscosity of said composition prior
to sterilizing.
39. The method of claim 34, wherein said stabilizer is an herbal
extract.
40. The method of claim 39, wherein said herbal extract is an
oil-soluble herbal extract.
41. The method of claim 40, wherein said herbal extract is selected
from the group consisting of chamomile, carrot root, echinacea
purpurea, fennel, ginseng, grape seed, grape skin, grapefruit,
guggalipids, harpogophytum, jasmine, marjoram, myrrh gum resin,
onion, pine bark, red clover flower, resveratrol, rosemary, sesame,
St. Johns wort, thyme, Uva Ursi (bearberry), borage seed oil, wild
borage seed oil, hesperedin, quercetin, kaempherol, genistein,
coumestrol, estriol, phytosterols, limonene, ethoxyquin,
hydroquinone, ubiquinone (coenzyme Q), lipoic acid, N-acetyl
cysteine, curcumin, basil leaf, bell pepper, dandelion root, date
palm fruit, licorice, tomato, myricetin, derivatives thereof, and
mixtures thereof.
42. The method of claim 40, wherein said herbal extract is selected
from the group consisting of chamomile, carrot root, echinacea
purpurea, fennel, ginseng, grape seed, grape skin, grapefruit,
guggalipids, harpogophytum, jasmine, marjoram, myrrh gum resin,
onion, pine bark, red clover flower, resveratrol, rosemary, sesame,
St. Johns wort, thyme, Uva Ursi (bearberry), borage seed oil, wild
borage seed oil, hesperedin, quercetin, kaempherol, genistein,
coumestrol, estriol, phytosterols, limonene, ethoxyquin,
hydroquinone, ubiquinone (coenzyme Q), lipoic acid, N-acetyl
cysteine, curcumin, derivatives thereof, and mixtures thereof.
43. The method of claim 40, wherein said herbal extract is selected
from the group consisting of dill, horseradish, oats, neem, beet,
broccoli, tea, pumpkin, soybean, barley, walnut, flax, ginseng,
poppy, avocado, pea, sesame, dandelion, wheat, nettle, cashew,
pineapple, apple, asparagus, Brazilnut, chickpea, grapefruit,
orange, cucumber, buckwheat, strawberry, ginko, tomato, blueberry,
cowpea, grape extracts, ivy horse chestnut, centella asiatica,
rosmarinic acid, glycyrrizinate derivatives, alpha bisabolol,
azulene, asiaticoside, sericoside, ruscogenin, escin, escolin,
betulinic acid, catechin, derivatives thereof, and mixtures
thereof.
44. The method of claim 34, wherein said stabilizer is curcumin or
a curcumin derivative.
45. The method of claim 44, wherein said stabilizer is selected
from the group consisting of curcumin, demethoxycurcumin,
bisdemethoxycurcumin, tetrahydrocurcumin,
tetrahydrodemethoxycurcumin, tetrahydrobisdemethoxycu- rcumin,
other curcumin metabolites, (4-hydroxy-3-methoxycinnamoyl)methane,
bis(4-hydroxycinnamoyl)methane, hexahydrocurcumin,
octahydrocurcumin, and mixtures thereof.
46. The method of claim 34, wherein said stabilizer is an alpha- or
beta-C.sub.1-C.sub.30 hydroxycarboxylic acid or salt thereof.
47. The method of claim 46, wherein said stabilizer is selected
from the group consisting of alpha- and beta-C.sub.1-C.sub.30
hydroxycarboxylic acids and salts thereof.
48. The method of claim 46, wherein said stabilizer is selected
from the group consisting of salicylic acid, alpha hydroxy acetic
acid, alpha hydroxybenzeneacetic acid, alpha hydroxypropionic acid,
alpha hydroxybutanoic acid, alpha hydroxyhexanoic acid, alpha
hydroxyoctanoic acid, alpha hydroxynonanoic acid, alpha
hydroxydecanoic acid, alpha hydroxyundecanoic acid, alpha
hydroxydodecanoic acid, alpha hydroxytetradecanoic acid, alpha
hydrocyhexadecanoic acid, alpha hydroxyoctadecanoic acid, alpha
hydroxyoctaeicosanoic acid, dicarboxylic alpha hydroxy acids,
dihydroxybutanedioic acid (tartaric acid), 2-hydroxybutanedioic
acid, 2-hydroxy propanedioic acid, 2-hydroxy hexanedioic acid,
2-hydroxy octanedioic acid, 2-hydroxy decanedioic acid, 2-hydroxy
dodecanedioic acid, 2-hydroxy myristicdioic acid, 2-hydroxy
palmiticdioic acid, tricarboxylic alpha hydroxy acid,
2-hydroxy-1,2,3,-propanetricarboxylic acid,
1-hydroxy-1,2,3-propanetricar- boxylic acid, and mixtures
thereof.
49. The method of claim 34, wherein said stabilizer is a
ceramide.
50. The method of claim 49, wherein said ceramide is selected from
the group consisting of Ceramide 1, Ceramide 3, Ceramide 6, and
mixtures thereof.
51. The method of claim 34, wherein said stabilizer is an
anti-inflammatory.
52. The method of claim 51, wherein said anti-inflammatory is
selected from the group consisting of beta-methasone 17-acetate,
indomethacin, ketoprofen, flufenamic acid, ibuprofen, diclofenace,
diflunisal, fenclofenac, naproxen, piroxidam, sulindac, and
mixtures thereof.
53. The method of claim 34, wherein said stabilizer is a
vasoconstrictor.
54. The method of claim 53, wherein said vasoconstrictor is
selected from the group consisting of papaverine, yohimbine,
visnadin, khellin, bebellin, nicotinate derivatives, and mixtures
thereof.
55. The method of claim 34, wherein said monomer is an
.alpha.-cyanoacrylate.
56. The method of claim 34, wherein said monomer is at least one
member selected from the group consisting of methyl cyanoacrylate,
ethyl cyanoacrylate, n-butyl cyanoacrylate, 2-octyl cyanoacrylate,
methoxyethyl cyanoacrylate, ethoxyethyl cyanoacrylate, hexyl
cyanoacrylate, dodecyl cyanoacrylate, butyl lactoyl cyanoacrylate,
butyl glycoloyl cyanoacrylate, ethyl lactoyl cyanoacrylate, and
ethyl glycoloyl cyanoacrylate.
57. The method of claim 34, wherein said stabilizer is present in
said composition in a concentration of from about 0.01 to about
10.0% by weight.
58. The method of claim 34, wherein said stabilizer is present in
said composition in a concentration of from about 0.01 to about
5.0% by weight.
59. The method of claim 34, wherein said composition has a total
volume in said container of less than 10 milliliters.
60. The method of claim 34, wherein said composition further
comprises at least one antioxidant stabilizer.
61. The method of claim 60, wherein said at least one antioxidant
stabilizer is selected from the group consisting of vitamin E and
derivatives thereof, vitamin K and derivatives thereof, vitamin C,
pentamethyl chromanol, non-phenolic antioxidants, octyl gallate,
and pentamethylbenzofuranol.
62. The method of claim 60, wherein said at least one antioxidant
stabilizer is pentamethyl chromanol.
63. A sterile composition made by the method of claim 34.
64. A polymerized film made by polymerizing the composition of
claim 1.
65. A method of treating tissue comprising: applying the
composition of claim 1 to tissue; and allowing the monomer to
polymerize to form a polymer film.
66. The method of claim 65, wherein said stabilizer is present in
said polymer film in an amount effective to promote wound healing.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] The present invention relates to monomer and polymer
adhesive and sealant compositions, and to their production and use
for industrial and medical applications. In particular, the present
invention relates to the incorporation of dual function agents in
adhesive compositions, such as to provide combined stabilization
properties to the composition and active agent properties to the
application surface such as to enhance the wound healing properties
of such compositions when used for medical purposes.
[0003] 2. Description of Related Art
[0004] Monomer and polymer adhesives are used in both industrial
(including household) and medical applications. Included among
these adhesives are the 1,1-disubstituted ethylene monomers and
polymers, such as the .alpha.-cyanoacrylates. Since the discovery
of the adhesive properties of such monomers and polymers, they have
found wide use due to the speed with which they cure, the strength
of the resulting bond formed, and their relative ease of use. These
characteristics have made the .alpha.-cyanoacrylate adhesives the
primary choice for numerous applications such as bonding plastics,
rubbers, glass, metals, wood, and, more recently, biological
tissues.
[0005] It is known that monomeric forms of .alpha.-cyanoacrylates
are extremely reactive, polymerizing rapidly in the presence of
even minute amounts of an initiator, including moisture present in
the air or on moist surfaces such as animal (including human)
tissue. Monomers of .alpha.-cyanoacrylates are anionically
polymerizable or free radical polymerizable, or polymerizable by
zwitterions or ion pairs to form polymers. Once polymerization has
been initiated, the cure rate can be very rapid.
[0006] Medical applications of 1,1-disubstituted ethylene adhesive
compositions include use as an alternate or an adjunct to surgical
sutures and/or staples in wound closure, as well as for covering
and protecting surface wounds such as lacerations, abrasions,
burns, stomatitis, sores, minor cuts and scrapes, and other wounds.
When an adhesive is applied to surfaces to be joined, it is usually
applied in its monomeric form, and the resultant polymerization
gives rise to the desired adhesive bond.
[0007] The industrial production of 1,1-disubstituted ethylene
monomer adhesive compositions has been optimized to provide
adhesives with rapid cure rates and high bond strengths. However,
the desire to provide an adhesive with a rapid cure rate has led to
problems with shelf-life. The shelf-life of these adhesives is
primarily related to stability (i.e., constancy of compositional
nature), uncured physical properties, rate of cure of the adhesive,
as well as final cured properties of the composition. For example,
the shelf-life of a monomeric .alpha.-cyanoacrylate composition is
related to the amount of time the composition can be stored before
unacceptable levels of polymerization occur. Unacceptable levels
are indicated by a level of polymerization product that reduces the
usefulness of the composition in the application for which it is
produced. It is well known that monomeric forms of
.alpha.-cyanoacrylates polymerize rapidly in the presence of even
minute amounts of an initiator, and that once polymerization has
been initiated, the rate of cure can be very rapid. Therefore, in
order to obtain a monomeric .alpha.-cyanoacrylate composition with
an extended shelf-life, polymerization inhibitors such as anionic
and free radical stabilizers are often added to the compositions.
However, addition of such stabilizers can result in substantial
retardation of the cure rate of the composition. Therefore, in the
production of industrial .alpha.-cyanoacrylate adhesives, the
amount of stabilizers added is minimized so that the cure rate is
not adversely affected.
[0008] Cyanoacrylate adhesives used in medical applications
preferably have a shelf-life of at least twelve months. In order to
achieve a useful shelf-life, anionic and free-radical stabilizers
are generally added to the monomer compositions.
[0009] As disclosed in U.S. Pat. Nos. 3,559,652 to Banitt et al.
and 5,582,834 to Leung et al., for example, suitable stabilizers
for medically useful .alpha.-cyanoacrylate compositions include
Lewis acids such as sulfur dioxide, nitric oxide, and boron
trifluoride, as well as free-radical stabilizers including
hydroquinone, monomethyl ether hydroquinone, nitrohydroquinone,
catechol, and monoethyl ether hydroquinone. The combination of the
two anionic stabilizers sulfur dioxide and sulfonic acid is also
known and is disclosed in, for example, British Patent Application
GB 2 107 328 A. However, the use of these two anionic stabilizers
in combination does not overcome the "speed loss" seen in other
1,1-disubstituted ethylene adhesive compositions.
[0010] In addition to having an extended shelf-life, cyanoacrylate
compositions for use in many medical applications should be
sterile. Due to the importance of achieving and maintaining
sterility of these compositions, when an additive, such as an
anionic or free-radical stabilizer, is added to an
.alpha.-cyanoacrylate composition, it should be added prior to
sterilization. However, regardless of the type and number of
additives, sterilization of .alpha.-cyanoacrylate adhesive
compositions is often difficult to achieve. For example, widely
practiced methods of sterilization, such as heat sterilization and
ionizing radiation, are often not suitable for use with monomeric
cyanoacrylate compositions. Problems arise due to polymerization of
the monomer during the sterilization process, even in the presence
of stabilizers. In many cases, sterilization-induced polymerization
is so severe that the resulting product is unusable. Furthermore,
even when the sterilized product is still useable, the shelf-life
at desired storage temperatures, such as under refrigerated
conditions or at room temperature, can be shortened to such a
degree that the product is not suitable for commercialization.
[0011] Methods currently used to package and sterilize
.alpha.-cyanoacrylate monomer compositions have been developed with
the recognition that, to improve efficiency and productivity, the
packaging and sterilizing steps should be performed in rapid
succession. However, these methods do not provide the desired
shelf-life of the adhesive compositions in all packaging
materials.
[0012] Furthermore, during sterilization, much or all of the
stabilizer can be consumed or converted to another compound. For
example, U.S. Pat. No. 5,530,037 to McDonnell et al. discloses that
when a low level of sulfur dioxide is used to stabilize a
cyanoacrylate composition, all of the sulfur dioxide is converted
to sulfuric acid during the sterilization process. Thus, although
polymerization during sterilization can be minimized by use of low
levels of sulfur dioxide, and shelf-life of he sterilized
.alpha.-cyanoacrylate adhesive composition can be increased,
shelf-life might be improved by the presence of increased amounts
of sulfur dioxide in the initial composition. Unfortunately, at
initial high levels of a stabilizer, the general performance of the
adhesive can be impaired and the shelf life provided still is less
than desired.
[0013] McDonnell et al. also teaches that the use of the free
radical stabilizers butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT), in combination with 100 parts per million
(final concentration) sulfur dioxide, are not effective at
stabilizing .alpha.-cyanoacrylate compositions during gamma
irradiation sterilization. Rather, they must be present in
concentrations substantially above 1000 parts per million or higher
in order to provide effective stabilization.
[0014] In addition, various phenolic stabilizers have been used for
stabilizing adhesive compositions. For instance, McDonnell et al.
teaches the use of a free radical stabilizer selected from phenolic
antioxidants (except for hydroquinone). U.S. Pat. No. 4,125,494 to
Schoenberg teaches the use of anionic inhibitors including phenolic
compounds such as hydroquinone, t-butyl catechol, pyrocatechol,
p-methoxyphenol, and the like. U.S. Pat. No. 4,724,177 to Russo
teaches the use of free radical stabilizers including hydroquinone,
monomethylether hydroquinone, nitrohydroquinone, and hydroquinone
monoethylether. U.S. Pat. No. 5,034,456 to Katsumura teaches the
use of radical polymerization inhibitors including hydroquinone,
hydroquinone monomethyl ether, catechol, pyrogallol and the like.
U.S. Pat. No. 4,321,180 to Kimura teaches the use of radical
polymerization inhibitors such as aryl alcohols, phenol, cresols,
hydroquinone, benzoquinone, .alpha.-naphthol, .beta.-naphthol,
catechol, pyrogallol, bisphenol-A, bisphenol-S,
2,6-di-tert-butylphenol, 2,6-di-tert-butylcresol,
2,2'-methylene-bis(4-me- thyl-6-tert-butylphenol),
4,4'-butylidene-bis(3-methyl-6-tert-butylphenol)- ,
4,4'-thiobis(3-methyl-6-tert-butylphenol), hydroquinone monomethyl
ether, 2-hydroxybenzophenone, phenylsalicylic acid, 1,3
,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl) benzene
and the like.
[0015] Thus, a need exists for improved monomer cyanoacrylate
adhesive compositions, for both industrial and medical uses, having
a longer shelf-life without sacrificing the performance of the
adhesive.
SUMMARY OF THE INVENTION
[0016] The present invention provides an improved monomeric
adhesive composition, wherein the adhesive composition comprise a
selected dual-function stabilizer. In particular embodiments, the
present invention provides a monomer-containing adhesive
composition comprising a polymerizable 1,1-disubstituted ethylene
monomer, such as .alpha.-cyanoacrylate monomer, and at least one
selected dual function stabilizer. The dual function stabilizer
provides, for example, stabilization effects to the composition,
and wound healing effects when utilized for medical purposes.
[0017] The combination of a polymerizable monomer with at least one
selected dual function stabilizer according to the present
invention provides an adhesive monomer composition with an enhanced
and extended shelf-life and enhanced wound healing properties as
compared to similar compositions lacking such additives. The
present invention also provides an adhesive monomer composition
with an enhanced and improved ability to withstand sterilization
processing, such as gamma or electron beam irradiation processing,
as compared to similar compositions lacking such additives. As used
herein "extended shelf-life" refers to a shelf-life of at least 12
months, preferably at least 18 months, and even more preferably at
least 30 months. Moreover, "enhanced wound healing capabilities" as
used herein refers to the well known ability of various additives
to increase the rate at which a wound heals, or to minimize the
nature or effects of a wound. For example, where the dual function
stabilizer is also an antioxidant, the antioxidant reduces free
radicals that may otherwise hinder the ability of a wound to heal.
Although it is known to add polymerization inhibitors (stabilizers)
to monomeric adhesive compositions, the superiority of the use of a
dual function stabilizer according to the present invention, to
provide added stability and/or to enhance wound healing, has not
been previously recognized.
[0018] The present invention also includes a process for enhancing
the wound healing properties of such adhesive compositions, and for
increasing the shelf-life of such adhesive compositions. The
enhancement of the wound healing properties of the compositions
includes combining a polymerizable monomer with a selected dual
function stabilizer, either by itself or in combination with
additional medicaments or other additives.
DETAILED DESCRIPTION OF EMBODIMENTS
[0019] According to the present invention, a stable monomeric
adhesive composition is manufactured by combining at least one
selected dual function stabilizer with a composition comprising a
monomer adhesive. The at least one selected dual function
stabilizer according to the present invention 1) may inhibit
polymerization of the monomer of the composition to a greater
extent than can be achieved in prior art compositions, particularly
during sterilization processing, and/or 2) may enhance the wound
healing properties of the adhesive when used in medical
applications.
[0020] The dual function stabilizer according to the present
invention can be selected from among a range of materials that
provide the desired stabilization and wound healing properties. For
example, the dual function stabilizer can be selected from herbal
extracts, alpha- and beta-C.sub.1-C.sub.30 hydroxycarboxylic acids,
ceramides, anti-inflammatories, vasoconstrictors, and mixtures
thereof.
[0021] According to embodiments, the dual function stabilizer can
be a selected herbal extract. Herbal extracts particularly suitable
for the present invention are antioxidants or free-radical
inhibitors. As used herein, an "antioxidant" means a compound that
prevents degradation caused by oxidation. Preferably, the herbal
extract is oil soluble rather than water soluble, although suitable
results may be achieved using herbal extracts that are both oil-
and water-soluble, as well as with herbal extracts that are not oil
soluble.
[0022] Examples of suitable herbal extracts that are oil soluble
include, but are not limited to, chamomile, carrot root, echinacea
purpurea, fennel, ginseng, grape seed, grape skin, grapefruit,
guggalipids, harpogophytum, jasmine, marjoram, myrrh gum resin,
onion, pine bark, red clover flower, resveratrol, rosemary, sesame,
St. Johns wort, thyme, Uva Ursi (bearberry), borage seed oil, wild
borage seed oil, hesperedin, quercetin, kaempherol, genistein,
coumestrol, estriol, phytosterols, limonene, ethoxyquin,
hydroquinone, ubiquinone (coenzyme Q), lipoic acid, N-acetyl
cysteine, curcumin, derivatives thereof, mixtures thereof, and the
like. Examples of suitable herbal extracts that are oil soluble and
water soluble include, but are not limited to, basil leaf, bell
pepper, dandelion root, date palm fruit, licorice, tomato,
myricetin, derivatives thereof, mixtures thereof, and the like.
Examples of suitable herbal extracts that are water soluble
include, but are not limited to, black tea extracts, blackberry,
black currant fruit, coffee seed, gingko leaf, green tea
polyphenyls (such as epicatechin gallate and epigallocaatechin
3-O-gallate), hawthorn berries, sage, strawberry, sweet pea,
vanilla fruit, neohesperidin, rutin, morin, chlorogenic acid,
glutathione, derivatives thereof, mixtures thereof, and the
like.
[0023] Herbal extracts particularly effective for sebum/oil control
include dill, horseradish, oats, neem, beet, broccoli, tea,
pumpkin, soybean, barley, walnut, flax, ginseng, poppy, avocado,
pea, sesame, dandelion, wheat, nettle, cashew, pineapple, apple,
asparagus, Brazilnut, chickpea, grapefruit, orange, cucumber,
buckwheat, strawberry, ginko, tomato, blueberry, cowpea and grape
extracts. Other herbal extracts also suitable are those of ivy
horse chestnut, centella asiatica, rosmarinic acid, glycyrrizinate
derivatives, alpha bisabolol, azulene and derivatives thereof,
asiaticoside, sericoside, ruscogenin, escin, escolin, betulinic
acid and derivatives thereof, and catechin and derivatives
thereof.
[0024] In embodiments, a preferred dual function stabilizer is
curcumin, or derivatives thereof such as curcuminoids. Curcumin,
also referred to as tumeric yellow, difeurloylmethane, or C. I.
Natural Yellow 3, provides the dual benefits of being a stabilizing
agent to the adhesive composition prior to its application, as well
as providing antimicrobial effects during and after application. In
addition, curcumin compounds provide a characteristic color to the
composition, which can assist in identifying where the adhesive
composition has been applied, to help ensure proper placement and
coverage. Suitable curcumin and curcumin derivatives include, but
are not limited to, curcumin, demethoxycurcumin,
bisdemethoxycurcumin, tetrahydrocurcumin,
tetrahydrodemethoxycurcumin, tetrahydrobisdemethoxycurcumin, other
curcumin metabolites, (4-hydroxy-3-methoxycinnamoyl)methane,
bis(4-hydroxycinnamoyl)methane, hexahydrocurcumin,
octahydrocurcumin, mixtures thereof, and the like.
[0025] According to other embodiments of the present invention, the
dual function stabilizer can be a selected alpha- or
beta-hydroxycarboxylic acid, such as alpha- and
beta-hydroxycarboxylic acids ranging from C.sub.2-C.sub.30. The
beta-hydroxycarboxylic acids are primarily exemplified by salicylic
acid and C.sub.1-C.sub.30 ester and salt derivatives. Examples of
suitable alpha-hydroxycarboxylic acids include but are not limited
to: alpha hydroxy acetic acid (glycolic acid), alpha
hydroxybenzeneacetic acid (mandelic acid), alpha hydroxypropionic
acid (lactic acid), alpha hydroxybutanoic acid, alpha
hydroxyhexanoic acid, alpha hydroxyoctanoic acid (alpha
hydroxycaprylic acid), alpha hydroxynonanoic acid, alpha
hydroxydecanoic acid, alpha hydroxyundecanoic acid, alpha
hydroxydodecanoic acid (alpha hydroxylauric acid), alpha
hydroxytetradecanoic acid, alpha hydrocyhexadecanoic acid, alpha
hydroxyoctadecanoic acid, alpha hydroxyoctaeicosanoic acid,
dicarboxylic alpha hydroxy acids, dihydroxybutanedioic acid
(tartaric acid), 2-hydroxybutanedioic acid (malic acid), 2-hydroxy
propanedioic acid, 2-hydroxy hexanedioic acid, 2-hydroxy
octanedioic acid, 2-hydroxy decanedioic acid, 2-hydroxy
dodecanedioic acid, 2-hydroxy myristicdioic acid, 2-hydroxy
palmiticdioic acid, tricarboxylic alpha hydroxy acid,
2-hydroxy-1,2,3,-propanetricarboxylic acid (citric acid),
1-hydroxy-1,2,3-propanetricarboxylic acid (isocitric acid) and
mixtures thereof.
[0026] C.sub.1-C.sub.30 esters and salts of alpha- and
beta-hydroxycarboxylic acids (e.g. potassium, sodium, ammonium,
triethanolammonium and the like salts) are also meant to be
included within the term "alpha- and beta-hydroxycarboxylic acid."
Depending on the pH of the composition, a mixture of the salt and
the acid may be present.
[0027] According to the present invention, preferred alpha
hydroxycarboxylic acids are monocarboxylic acids, in order to
improve skin penetration and efficacy. Even more preferably, the
hydroxy acid is in embodiments chosen from lactic acid, glycolic
acid, mandelic acid, and mixtures thereof to optimize the efficacy
of compositions by increasing percutaneous absorption. Most
preferred is the L-form of an alpha hydroxycarboxylic acid.
[0028] Ceramides useful for the present invention are sphingolipids
or phytosphingolipids including Ceramide 1, Ceramide 3and Ceramide
6.
[0029] Anti-inflammatories of the present invention are illustrated
by corticoids such as beta-methasone 17-acetate, indomethacin,
ketoprofen, flufenamic acid, ibuprofen, diclofenace, diflunisal,
fenclofenac, naproxen, piroxidam and sulindac. Vasoconstrictors are
illustrated by compounds such as papaverine, yohimbine, visnadin,
khellin, bebellin and nicotinate derivatives. Other substances
within one or more of the above categories of actives include
resorcinol, azelaic acid, oxamic acid and cyoctol.
[0030] The amount of dual function stabilizer that is added to the
monomer composition depends on the monomer to be stabilized, the
stabilizer being selected, and/or the packaging material to be used
for the composition. Preferably, the dual function stabilizers of
the present invention may be included in an amount of from about
0.00001 to about 40%, preferably from about 0.01 to about 20%,
optimally from about 0.1 to about 10% and in some instances from
about 1 to about 8% by weight of the composition. Of course, herbal
extracts are usually employed at much lower levels than for
instance the hydroxycarboxylic acids. Thus, the amount of herbal
extracts may range from about 0.0001 to about 1%, preferably from
about 0.001 to about 0.5% by weight. Preferably the amount of the
hydroxycarboxylic acid component, when present in the composition
according to the invention, is from about 0.5% to about 20%, more
preferably from about 1% to about 15%, and most preferably from
about 3.0% to about 12.0% by weight of the composition.
[0031] However, depending upon the desired stabilization and wound
healing effects, lower amounts of the dual function stabilizer can
be used. Thus, for example, the dual function stabilizer can be
added in an amount of from about 0.01 to about 10 percent or more,
preferably up to about 5 percent or more or 2.0 percent or more by
weight based on the monomer. Contents outside of these ranges can
be used, in embodiments, as desired. Thus, for example, where the
antioxidants stabilizer is a higher molecular weight compound,
greater amounts of the antioxidant can be used to obtain the
desired result.
[0032] Preferably, according to the present invention, the dual
function stabilizer is included in the composition in an amount not
only to provide effective stabilization of the monomeric adhesive
composition, but also to provide wound healing properties to the
composition. Thus, for example, the dual function stabilizer is
included in an amount that provides sufficient residual antioxidant
stabilizer in a formed polymeric material, such that the
antioxidant can diffuse out of the formed polymer over time. By
such diffusion, the stabilizer is made available to an adjacent
tissue and/or a surrounding environment to impart wound healing
properties.
[0033] As used herein an amount of dual function stabilizer
sufficient or effective "to stabilize" the monomer composition
refers to an amount of stabilizer sufficient to prevent the
viscosity of a sterilized monomer composition from increasing to
more than 200%, and preferably 150%, of the composition's initial
viscosity after sterilization. Suitable monomer composition
stability, in terms of composition viscosity, according to the
present invention is disclosed in U.S. patent application Ser. No.
09/374,207 filed Aug. 12, 1999, the entire disclosure of which is
incorporated herein by reference.
[0034] An indication of premature polymerization in
1,1-disubstituted ethylene monomer compositions, such as
.alpha.-cyanoacrylate monomer compositions in particular, is an
increase in viscosity of the composition over time. That is, as the
composition polymerizes, the viscosity of the composition
increases. If the viscosity becomes too high, i.e., too much
premature polymerization has occurred, the composition becomes
unsuitable for its intended use or becomes very difficult to apply.
Thus, while some polymerization or thickening of the composition
may occur, such as can be measured by changes in viscosity of the
composition, such change is not so extensive as to destroy or
significantly impair the usefulness of the composition. However,
the present invention, by providing a dual function stabilizer in
the composition stored in the container, decreases or prevents the
premature polymerization of the composition, and thereby provides
better control over the viscosity of the composition.
[0035] In embodiments of the present invention, the dual function
stabilizer is included in the composition in an amount effective to
provide effective stabilization of the composition. Thus, for
example, the dual function stabilizer is contained in an amount
effective to stabilize the composition over a desired shelf-life of
the product, and/or to stabilize the composition during and after
any applicable sterilization procedure. A particular advantage of
the stabilizers is that they provide effective stabilization of the
composition during sterilization procedures, such as irradiation,
dry heat, and/or chemical sterilization processes. Accordingly, and
as necessary, the amount of the dual function stabilizer added to
the composition can be varied depending upon, for example, the
projected shelf-life of the composition and/or the kind and degree
of selected sterilization processing. Such selection and variation
of the stabilizer can be performed by one of ordinary skill in the
art with only routine experimentation.
[0036] In embodiments of the present invention, particularly where
the composition is to be used as a wound dressing or is otherwise
being applied to tissue, the dual function stabilizer can be
included in the composition for its wound healing properties as
well as for its stabilization properties. In these embodiments, if
desired, the amount of the stabilizer contained in the composition
can be increased, so that an effective amount of the stabilizer
remains present in the resultant polymer. When so present, the dual
function stabilizer is generally released or diffuses from the
polymer, either immediately or over time, into the tissue.
Accordingly, one or more of the above-described additives can be
included in the composition for their wound-healing effects.
[0037] In addition, according to the present invention, the
above-described dual function stabilizers can, additionally or
alternatively, be included in a container that is used to contain
polymerizable monomer adhesive compositions, such as
1,1-disubstituted adhesive compositions and cyanoacrylate adhesive
compositions. The benefits of such inclusion, as well as a
description of methods of including materials in the container
itself, are disclosed in U.S. patent application Ser. No.
09/657,913, filed Sep. 8, 2000, the entire disclosure of which is
incorporated herein by reference. The methods disclosed therein for
antioxidants and other stabilizers are also equally applicable to
the dual function stabilizers of the present invention. Similar
disclosure is also included in U.S. patent application Ser. No.
09/430,289, filed Oct. 29, 1999, the entire disclosure of which is
incorporated herein by reference.
[0038] According to the present invention, the container can be any
suitable container used to contain a polymerizable monomeric
adhesive composition. Thus, the container can be formed out of any
suitable material, and in any shape, size and/or construction, as
desired. Suitable container constructions are disclosed, for
example, in the above-referenced co-pending U.S. patent application
Ser. Nos. 09/430,289 and 09/657,913, the entire disclosure of which
is incorporated herein by reference.
[0039] In embodiments, the method of the present invention further
comprises sterilizing the 1,1-disubstituted ethylene monomer
composition and/or its packaging, either prior to, or subsequent
to, dispensing into the container. Suitable sterilization methods
according to the present invention are disclosed in U.S. patent
application Ser. No. 09/374,207 filed Aug. 12, 1999, the entire
disclosure of which is incorporated herein by reference.
[0040] Sterilization of the monomer composition and/or its
packaging can be accomplished by techniques known to one of
ordinary skill in the art, and is preferably accomplished by
methods including, but not limited to, chemical, physical, and/or
irradiation methods. Examples of chemical methods include, but are
not limited to, exposure to ethylene oxide or hydrogen peroxide
vapor. Examples of physical methods include, but are not limited
to, sterilization by heat (dry or moist) or retort canning.
Examples of irradiation methods include, but are not limited to,
gamma irradiation, electron beam irradiation, and microwave
irradiation. A preferred method is electron beam irradiation, as
described in U.S. Pat. No. 6,143,805, the entire disclosure of
which is incorporated herein by reference, as well as gamma
irradiation. The composition must show low levels of toxicity to
living tissue during its useful life. In preferred embodiments of
the present invention, the composition is sterilized to provide a
Sterility Assurance Level (SAL) of at least 10.sup.-3. In
embodiments, the Sterility Assurance Level may be at least
10.sup.-4, or may be at least 10.sup.-5, or may be at least
10.sup.-6.
[0041] According to the invention, the combination of at least one
dual function stabilizer provides sufficient inhibition of
polymerization of the monomer (i.e., stabilization of the
composition) that sterility can be achieved without the
unacceptable levels of polymerization or increases in cure rate due
to over-stabilization that result from methods disclosed in the
prior art. For example, sterilized compositions according to
embodiments of the present invention show an increase in viscosity
of no more than 300%, and preferably less than 150%, as a result of
sterilization. Viscosity levels can be determined by known
techniques. For example, viscosity can be determined at room
temperature (approximately 21-25.degree. C.) using a Brookfield
Cone-Plate Viscometer. The instrument is standardized using a
Viscosity Reference Standard in the same range as the sample to be
tested. Each sample is measured three times, and an average value
determined and recorded.
[0042] Preferred monomer compositions of the present invention, and
polymers formed therefrom, are useful as tissue adhesives, sealants
for preventing bleeding or for covering open wounds, and in other
absorbable and non-absorbable biomedical applications. They find
uses in, for example, apposing surgically incised or traumatically
lacerated tissues; retarding blood flow from wounds; dressing
burns; dressing skin or other superficial or surface wounds (such
as abrasions, chaffed or raw skin, ulceration and/or stomatitis);
hernia repair; meniscus repair; and aiding repair and re-growth of
living tissue. Compositions of the present invention, and polymers
formed therefrom, are also useful in industrial and home
applications, for example in bonding rubbers, plastics, wood,
composites, fabrics, and other natural and synthetic materials.
[0043] The monomer (including prepolymeric) adhesive composition
may include one or more polymerizable monomers. Preferred monomers
that may be used in this invention are readily polymerizable, e.g.
anionically polymerizable or free radical polymerizable, or
polymerizable by zwitterions or ion pairs to form polymers. Such
monomers include those that form polymers, that may, but do not
need to, biodegrade. Such monomers are disclosed in, for example,
U.S. Pat. Nos. 5,328,687 and 5,928,611 to Leung et al., U.S. patent
application Ser. No. 09/430,177, filed on Oct. 29, 1999, and U.S.
Pat. No. 6,183,593, which are hereby incorporated in their entirety
by reference herein. Preferred monomers include 1,1-disubstituted
ethylene monomers, such as .alpha.-cyanoacrylates including, but
not limited to, alkyl .alpha.-cyanoacrylates having an alkyl chain
length of from about 1 to about 20 carbon atoms or more, preferably
from about 3 to about 8 carbon atoms.
[0044] The .alpha.-cyanoacrylates of the present invention can be
prepared according to several methods known in the art. U.S. Pat.
Nos. 2,721,858, 3,254,111, 3,995,641, and 4,364,876, each of which
is hereby incorporated in its entirety by reference herein,
disclose methods for preparing .alpha.-cyanoacrylates.
[0045] Preferred .alpha.-cyanoacrylate monomers used in this
invention include methyl cyanoacrylate, ethyl cyanoacrylate,
n-butyl cyanoacrylate, 2-octyl cyanoacrylate, methoxyethyl
cyanoacrylate, ethoxyethyl cyanoacrylate, dodecyl cyanoacrylate,
2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, 3-methoxybutyl
cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl
cyanoacrylate, 1-methoxy-2-propyl cyanoacrylate, hexyl
cyanoacrylate, or dodecylcyanoacrylate.
[0046] Suitable cyanoacrylates for use in the present invention
also include, but are not limited to, alkyl ester cyanoacrylate
monomers such as those having the formula 1
[0047] wherein R.sub.1 and R.sub.2 are, independently H, a
straight, branched or cyclic alkyl, or are combined together in a
cyclic alkyl group, and R.sub.3 is a straight, branched or cyclic
alkyl group. Preferably, R.sub.1is H or a C.sub.1, C.sub.2 or
C.sub.3 alkyl group, such as methyl or ethyl; R.sub.2 is H or a
C.sub.1, C.sub.2 or C.sub.3 alkyl group, such as methyl or ethyl;
and R.sub.3 is a C.sub.1-C.sub.16 alkyl group, more preferably a
C.sub.1-C.sub.10 alkyl group, such as methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, nonyl or decyl, and even more
preferably a C.sub.2, C.sub.3 or C.sub.4 alkyl group. Such alkyl
ester cyanoacrylates and other suitable monomers are disclosed in,
for example, U.S. patent application Ser. Nos. 09/630,437, filed
Aug. 2, 2000, and 09/919,877, filed Aug. 2, 2001, the entire
disclosures of which are incorporated herein by reference.
[0048] Examples of preferred alkyl ester cyanoacrylates include,
but are not limited to, butyl lactoyl cyanoacrylate (BLCA), butyl
glycoloyl cyanoacrylate (BGCA), ethyl lactoyl cyanoacrylate (ELCA),
and ethyl glycoloyl cyanoacrylate (EGCA). BLCA may be represented
by the above formula, wherein R.sub.1 is H, R.sub.2 is methyl and
R.sub.3 is butyl. BGCA may be represented by the above formula,
wherein R.sub.1 is H, R.sub.2 is H and R.sub.3 is butyl. ELCA may
be represented by the above formula, wherein R.sub.1 is H, R.sub.2
is methyl and R.sub.3 is ethyl. EGCA may be represented by the
above formula, wherein R.sub.1 is H, R.sub.2 is H and R.sub.3 is
ethyl.
[0049] The composition may optionally also include at least one
other plasticizing agent that assists in imparting flexibility to
the polymer formed from the monomer. The plasticizing agent
preferably contains little or no moisture and should not
significantly affect the stability or polymerization of the
monomer. Examples of suitable plasticizers include but are not
limited to isopropyl myristate, isopropyl palimtate, tributyl
citrate, acetyl tri-n-butyl citrate (ATBC), polymethylmethacrylate,
polydimethylsiloxane, polyester glutarates; polyester adipates;
polyester sebacates; and others as listed in U.S. Pat. No.
6,183,593, the disclosure of which is incorporated in its entirety
by reference herein.
[0050] The composition may also optionally include at least one
thixotropic agent. Suitable thixotropic agents are known to the
skilled artisan and include, but are not limited to, silica gels
such as those treated with a silyl isocyanate, and optionally
surface treated titanium dioxide. Examples of suitable thixotropic
agents and thickeners are disclosed in, for example, U.S. Pat. No.
4,720,513, and U.S. patent application Ser. No. 09/374,207 filed
Aug. 12, 1999, the disclosures of which are hereby incorporated in
their entireties by reference herein.
[0051] The composition may optionally also include thickeners.
Suitable thickeners may include poly (2-ethylhexy methacrylate),
poly(2-ethylhexyl acrylate) and others as listed in U.S. patent
application Ser. No. 09/472,392 filed Dec. 23, 1999, the disclosure
of which is incorporated by reference herein in its entirety.
[0052] The composition may also optionally include at least one
natural or synthetic rubber to impart impact resistance. Suitable
rubbers are known to the skilled artisan. Such rubbers include, but
are not limited to, dienes, styrenes, acrylonitriles, and mixtures
thereof. Examples of suitable rubbers are disclosed in, for
example, U.S. Pat. Nos. 4,313,865 and 4,560,723, the disclosures of
which are hereby incorporated in their entireties by reference
herein.
[0053] The composition may optionally also include one or more
additional stabilizers, such as both at least one anionic vapor
phase stabilizer and at least one anionic liquid phase stabilizer.
These stabilizing agents may further inhibit premature
polymerization. Suitable stabilizers may include those listed in
U.S. Pat. No. 6,183,593, the disclosure of which is incorporated by
reference herein in its entirety. Suitable stabilizing agents also
include any of the known anionic and free radical stabilizing
agents.
[0054] Where an one or more additional stabilizers is included in
the compositions, a preferred additional stabilizer in embodiments
is an antioxidant stabilizer, such as those disclosed in U.S.
patent application Ser. No. 09/657,913, filed Sep. 8, 2000, the
disclosure of which is incorporated by reference herein in its
entirety.
[0055] Suitable antioxidant stabilizer can be selected from among
known antioxidants, including, but not limited to, vitamin E
(C.sub.29H.sub.50O.sub.2) (including alpha-tocopherol
(C.sub.29H.sub.50O.sub.2), beta-tocopherol
(C.sub.28H.sub.48O.sub.2), gamma-tocopherol
(C.sub.28H.sub.48O.sub.2) and delta-tocopherol
(C.sub.27H.sub.46O.sub.2) and derivatives thereof, vitamin K
(including phylloquinone (C.sub.31H.sub.46O.sub.2), menaquinone
(e.g. menaquinone 4 (C.sub.31H.sub.40 O.sub.2)), and menadione
(C.sub.11H.sub.8O.sub.2) and derivatives thereof, including but not
limited to vitamin K.sub.1, chromanol and vitamin K.sub.1
chromenol, vitamin C (ascorbic acid (C.sub.6H.sub.8O.sub.6)) and
derivatives thereof, pentamethyl chromanol
(C.sub.14H.sub.20O.sub.2), non-phenolic antioxidants, octyl gallate
(C.sub.14H.sub.20O.sub.5) and pentamethyl benzofuranol
(C.sub.13H.sub.18O.sub.2). A preferred vitamin E antioxidant is any
of the series of IRGANOX.RTM. brand vitamin E (available from Ciba
Specialty Chemical Co.). A preferred pentamethyl chromanol is
2,2,5,7,8-pentamethyl-6-chromanol. Derivatives of the described
compounds, particularly where the moieties are benzopyranols or
benzofuranols, are also suitable.
[0056] Other suitable antioxidant stabilizers include compounds of
the following formula: 2
[0057] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
independently selected from hydrogen, substituted alkyl or
unsubstituted alkyl groups having from, for example, 1 to about 20
carbon atoms. Furthermore, suitable compounds include those of the
above formula where R.sup.2 and R.sup.3, and/or R.sup.4 and
R.sup.5, may optionally form cyclic groups having from about 2 to
about 40 carbon atoms, preferably from about 2 or about 3 to about
6 or about 8 carbon atoms.
[0058] The compositions may also include pH modifiers to control
the rate of degradation of the resulting polymer, as disclosed in
U.S. patent application Ser. No. 08/714,288, filed Sep. 18, 1996,
the entire disclosure of which is hereby incorporated by reference
herein in its entirety.
[0059] Compositions of the present invention may also include at
least one biocompatible agent effective to reduce active
formaldehyde concentration levels produced during in vivo
biodegradation of the polymer (also referred to herein as
"formaldehyde concentration reducing agents"). Preferably, this
component is a formaldehyde scavenger compound. Examples of
formaldehyde scavenger compounds useful in this invention include
sulfites; bisulfites; mixtures of sulfites and bisulfites, etc.
Additional examples of formaldehyde scavenger compounds useful in
this invention and methods for their implementation can be found in
U.S. Pat. Nos. 5,328,687, 5,514,371, 5,514,372, 5,575,997,
5,582,834 and 5,624,669, all to Leung et al., which are hereby
incorporated herein by reference in their entireties.
[0060] To improve the cohesive strength of adhesives formed from
the compositions of this invention, difunctional monomeric
cross-linking agents may be added to the monomer compositions of
this invention. Such crosslinking agents are known. U.S. Pat. No.
3,940,362 to Overhults, which is hereby incorporated herein in its
entirety by reference, discloses exemplary cross-linking
agents.
[0061] The compositions of this invention may further contain a
fibrous reinforcement and colorants such as dyes, pigments, and
pigment dyes. Examples of suitable fibrous reinforcements include
PGA microfibrils, collagen microfibrils, and others as described in
U.S. Pat. No. 6,183,593, the disclosure of which is incorporated by
reference herein in its entirety.
[0062] The polymerizable compositions useful in the present
invention may also further contain one or more medicaments,
preferably one or more non-antioxidant medicaments. Suitable
medicaments include, but are not limited to, antibiotics,
antimicrobials, antiseptics, bacteriocins, bacteriostats,
disinfectants, steroids, anesthetics, antifungal agents,
anti-inflammatory agents (other than the dual function stabilizers
of the present invention), antibacterial agents, antiviral agents,
antitumor agents, growth promoting substances, antioxidants (other
than the dual function stabilizers of the present invention), or
mixtures thereof. Suitable specific medicaments are disclosed in,
for example, U.S. patent application Ser. No. 09/430,177, filed
Oct. 29, 1999, the entire disclosure of which is incorporated
herein by reference.
[0063] The polymerizable compositions useful in the present
invention may also further contain one or more preservatives. The
preservatives may be present, for example, for prolonging the
storage life of the composition and/or for destroying and/or
usefully suppressing the growth or metabolism of a variety of
microscopic or submicroscopic life forms, either in the composition
itself, or in or on a substrate to which the composition may be
applied. Suitable preservatives, and methods for selecting them and
incorporating them into adhesive compositions, are disclosed in
U.S. patent application Ser. No. 09/430,180, the entire disclosure
of which is incorporated herein by reference.
[0064] In embodiments of the present invention, the composition
and/or its applicator may contain materials such as a
polymerization initiator, accelerator, rate-modifier, and/or
cross-linking agent for initiating polymerization and/or
cross-linking of the polymerizable monomer material. Suitable
materials and applicators and packaging systems are disclosed in
U.S. Pat. No. 5,928,611 and U.S. patent application Ser. Nos.
09/430,177, 09/430,176, 09/430,289, 09/430,290, and 09/430,180
filed Oct. 29, 1999; 09/343,914 filed Jun. 30, 1999; 09/385,030
filed Aug. 30, 1999; and 09/176,889 filed Oct. 22, 1998; the entire
disclosures of which are incorporated herein by reference.
EXAMPLES
Example 1
[0065] A 2-octyl Cyanoacrylate monomer (2-OCA) composition is
prepared by the addition of 0.5 wt. percent of curcumin. The
monomer composition is stirred until all the curcumin is dissolved.
The curcumin dissolves in the 2-OCA to provide a medically
acceptable monomer composition. The formulation is suitable for
evaluated of its wound healing property.
Example 2
[0066] Pigs are anesthetized and the entire dorsal, thoracic region
is shaved using an electric clipper. Portions of the area are
shaved using a single edge razor and soap as a lubricant. Care is
taken to avoid abrasions during shaving. The shaved surface is
antiseptically prepared using a non-antimicrobial soap solution
followed by 3 rinses with water and a final rinse with 70%
isopropyl alcohol. Wounds measuring approximately 0.7 cm.times.0.7
cm are made on the skin with the aid of a Dermatome. Wounds are
made to a depth of approximately 300 .mu.m.
[0067] Formulations are randomly applied to the wounds. The
formulations include a control 2-OCA formulation (similar to the
formulation of Example 1 but without added curcumin); the 2-OCA
formulation of Example 1; TEGADERM.RTM.; and no formulation (i.e.,
the wound is exposed to air).
[0068] After a 4-day exposure period, animals are anesthetized
under 3% isoflurane and five wounds per treatment group are excised
using a dermatome set to cut 700 .mu.m deep. The harvested wounds
are subjected to 0.5mol/L NaBr for 24 hours at 37 .+-.2.degree. C.
in 6-well plates. After incubation, the dermis and epidermis are
separated using fine forceps, and the epidermal integrity is
determined by macroscopic examination of the layer for
interruptions in the continuum of the epidermal sheet. This
procedure is repeated on days 5-8 after the initial injury. The
excision sites are dressed with the test article to stop the
bleeding and seal the wound. Animals are euthanized with a
veterinary barbiturate after collection of test and control sites
on day 8.
[0069] The table below shows the results of the testing, showing
the percent of the wound that is completely re-epithelialized
(i.e., healed).
1 Days Post- 2-OCA 2-OCA w/ Air Treatment control curcumin TEGADERM
.RTM. exposed 4 0 60 0 0 5 20 100 20 0 6 80 100 80 0 7 80 100 100
100 8 80 100 80 80
Example 3
[0070] A 2-octyl Cyanoacrylate monomer (2-OCA) composition is
prepared by the addition of 3000 ppm tetrahydrocurcumin (THC). The
monomer composition is stirred until all the THC dissolves. A 2-OCA
formulation without added THC is used as a control. Fluorinated
high-density polyethylene bottles are filled with the formulations
and subsequently exposed to electron beam sterilization at 15 KGy.
The sterilized bottles are maintained at elevated temperature for
12 days. The stability of the formulations are evaluated at 6 and
12 days post sterilization for changes in viscosity. The results
are shown in the following Table.
2 Change change change in viscosity in viscosity in viscosity
Formulation post e-beam after 6 days after 12 days 2-OCA + 3000 ppm
1.3 cPs 4.7 cPs 57.8 cPs THC 2-OCA control 1.1 cPs 5.2 cPs 56.2
cPs
Example 4
[0071] A 2-octyl Cyanoacrylate monomer (2-OCA) composition is
prepared by the addition of 2500 ppm of tetrahydrocurcumin (THC)
and 2500 ppm of 2,2,5,7,8-pentamethyl-6-chromanol. The monomer
composition is stirred until both the THC and chromanol dissolve. A
2-OCA formulation without added THC or chromanol is used as a
control. Fluorinated high-density polyethylene bottles are filled
with the formulations and subsequently exposed to electron beam
sterilization at 15 KGy. The bottles are maintained at elevated
temperature for 12 days. The stability of the formulations are
evaluated at 6 and 12 days post sterilization for changes in
viscosity. The results are shown in the following table.
3 Change in Change in Change in viscosity viscosity viscosity after
Formulation Post ebeam after 6 days 12 days 2-OCA + 2500 ppm THC +
0.3 cPs 3.7 cPs 34.8 cPs 2500 ppm of chromanol 2-OCA + 5000 ppm 0.7
cPs 4.2 cPs 45.5 cPs of chromanol 2-OCA 1.6 cPs 7.8 cPs 81 cPs
[0072] While the invention has been described with reference to
preferred embodiments, the invention is not limited to the specific
examples given, and other embodiments and modifications can be made
by those skilled in the art without departing from the spirit and
the scope of the invention.
* * * * *